Cleaver J E, Afzal V, Feeney L, McDowell M, Sadinski W, Volpe J P, Busch D B, Coleman D M, Ziffer D W, Yu Y, Nagasawa H, Little J B
Department of Dermatology, University of California at San Francisco, 94143-0750, USA.
Cancer Res. 1999 Mar 1;59(5):1102-8.
The xeroderma pigmentosum (XP) variant (XPV) is a form of XP that has normal excision repair but shows defective DNA replication after UV irradiation. In developing various transformed fibroblast cell lines from these patients, we have found that there are significant phenotypic changes in transformed cells that seem to correlate with inactivation of p53. After transformation with SV40, XPV cell lines are only slightly UV sensitive, like their primary counterparts, but their sensitization with caffeine and the induction of sister chromatid exchanges (SCEs) by UV irradiation are greatly enhanced. After transformation by HPV16 E7, which targets the retinoblastoma cell cycle regulatory gene, there is no change in the UV sensitivity of XPV cells; but, when transformed by HPV16 E6 or E6 and E7 combined, there is a large increase in UV sensitivity and in the induction of SCEs. These changes are not associated with any detectable changes in the reactivation of an externally irradiated luciferase expression vector, the excision of cyclobutane pyrimidine dimers from bulk DNA, or unscheduled DNA synthesis and, therefore, do not involve excision repair. We suggest that if SCEs represent homologous recombination between sister chromatids, then in the absence of p53 function, the DNA chain arrest typical of UV-damaged XPV cells initiates strand exchange during recovery. In untransformed cells with normal p53, the preferred mode of recovery would then be replication bypass. The symptoms of elevated solar carcinogenesis in XPV patients may, therefore, be associated with increased genomic instability in cells of the skin in which p53 is inactivated by UV-induced mutations.
着色性干皮病（XP）变异型（XPV）是XP的一种形式，其切除修复正常，但紫外线照射后DNA复制存在缺陷。在从这些患者中培养各种转化的成纤维细胞系时，我们发现转化细胞中存在显著的表型变化，这似乎与p53的失活相关。用SV40转化后，XPV细胞系仅对紫外线有轻微敏感性，与其原代细胞相似，但它们对咖啡因的敏感性以及紫外线照射诱导的姐妹染色单体交换（SCEs）大大增强。用靶向视网膜母细胞瘤细胞周期调控基因的HPV16 E7转化后，XPV细胞对紫外线的敏感性没有变化；但是，当用HPV16 E6或E6与E7联合转化时，紫外线敏感性和SCEs的诱导大幅增加。这些变化与外部照射的荧光素酶表达载体的再激活、从大量DNA中切除环丁烷嘧啶二聚体或非预定DNA合成的任何可检测变化均无关，因此不涉及切除修复。我们认为，如果SCEs代表姐妹染色单体之间的同源重组，那么在缺乏p53功能的情况下，紫外线损伤的XPV细胞典型的DNA链停滞在恢复过程中启动链交换。在具有正常p53的未转化细胞中，恢复的首选模式则是复制绕过。因此，XPV患者皮肤癌发生增加可能与皮肤细胞中基因组不稳定性增加有关，其中p53因紫外线诱导的突变而失活。
